A fundamental aspect of age-related bone loss is the decreased proliferative capacity and impaired differentiation of osteoblasts in the bone of older individuals. Telomeres shorten with age in most human tissues, including bone, and since telomere shortening is a cause of cellular replicative senescence in cultured cells, including osteoblasts and mesenchymal stem cells (MSCs), it is likely that telomere status in MSCs is a critical component of bone formation. Osteoporosis is common in the Werner (Wrn) and Dyskeratosis congenita (DC) premature aging syndromes. One of the targets of the Wrn helicase is telomeric DNA, but the long telomeres and abundant telomerase in mice minimize the need for WRN at telomeres, and thus Wrn knockout mice are healthy. In a model of accelerated aging that combines the Wrn mutation with the shortened telomeres of telomerase (Terc) knockout mice, synthetic defects in proliferative tissues, including bone, have been observed. It is hypothesized that deficiencies in genome maintenance molecules such as TERC and WRN cause a low bone mass phenotype and microarchitectural abnormalities of bone by impairing the ability of MSCs to differentiate into osteoblasts. It is further hypothesized that effective osteoblast differentiation depends on the presence of functional MSCs and hematopoietic stem cells (HSCs). Using micro-CT analysis and bone histomorphometry, this proposal will establish the relationship between the WRN and TERC molecules and structural bone fidelity, including microarchitecture and bone density. We will determine if age-related bone abnormalities in Wrn-/-, Terc-/- and Wrn -/- Terc-/- mice are related to deficiencies in osteoblast differentiation and/or increased osteoclastogenic potential, and will examine whether anabolic defects due to MSC impairment in mutant mice are associated with replicative senescence and/or telomere shortening/uncapping. We will also assess the contributions of MSCs and HSCs to osteoblast differentiation by selective and nonselective bone marrow transplantation of these cellular progenitors and analysis of their ability to reduce age-related osteoporotic changes. A consequence and major clinical challenge in the elderly is osteoporosis and associated high risk of fracture. The Wrn-/-Terc -/- mutant mouse recapitulates senile osteoporosis characterized by decreased bone-forming capacity and provides a system to test stem cell replacement for amelioration of age-related osteoporosis.